Various processes are known for the production of 21-hydroxypregna-4,16-diene-3,20-diones.
U.S. Pat. No. 3,839,369 claims a process for preparing a 21-hydroxypregna-4,9(11),16-triene-3,20-dione-type steroid by heating the corresponding 17-nitrate ester. The present invention does not go thru a 17.alpha.-hydroxy steroid or involve a nitrate ester.
U.S. Pat. No. 3,493,563 discloses a process for preparing a 21-hydroxypregna-4,9(11),16-triene-3,20-dione-type steroid by dehydrating with thionyl chloride or phosphorus oxychloride the corresponding 17.alpha.,21-dihydroxy-20-keto steroid. The process of the present invention introduces the double bond at C-16 during the addition of the two carbon side chain at C-17 starting with an androstenedione-type steroid.
U.S. Pat. No. 3,631,076 claims a process for preparing a 16-unsaturated steroid by reacting a 17.alpha.-alkanoyloxy or 17-aroyloxy corticoid with an alkali metal or alkaline earth metal salt of a lower alkanoic or aromatic acid. The process of the present invention does not produce or proceed thru a corticoid but produces the 16-unsaturated steroid from a 17(20)-unsaturated-21-aldehyde (IV).
U.S. Pat. Nos. 3,281,415 and 3,541,082 disclose processes to produce .DELTA..sup.16 -pregnanes from C-20 hydroperoxides which are produced by photosensitized oxidation of the corresponding .DELTA..sup.17(20) -steroidal olefins. The present invention involves neither photosensitized oxidation nor hydroperoxides.
German Offenlegungsschrift No. 2,603,266 discloses a process for adding the 21-hydroxy-20-keto side chain to a 17-keto steroid. The process does not proceed along the synthetic pathway of the present invention, nor does it produce the 21-aldehyde (IV) intermediate or the C-16 unsaturated compounds of the present invention.
U.S. Pat. No. 4,041,055 claims a process for adding a 2 carbon side chain to a 17-keto steroid via ethisterone-type compounds and does not produce C-16 unsaturated compounds.
J. Ficini et al. in Tetrahedron Letters 8, 937 (1968) describe the synthesis of various lithium chlorovinyl ethers and the reactions of lithiated cis-2-chloro-1-ethoxyethylene with cyclohexanone to give an .alpha.,.beta.-unsaturated .alpha.-chloroaldehyde. The yield quoted was about 40%, see page 940. When ketones are reacted with strongly basic compounds such as the lithium compounds of Ficini a significant amount of enolization of the ketone is expected and therefore upon work up a significant amount of starting material is regenerated which should significantly reduce the yield. Therefore, the low yield, about 40% obtained by Ficini is expected. Surprisingly and unexpectedly when either trans-2-chloro-2-lithio-1-ethoxyethylene (VIb) or the cis-trans mixture (VIa and VIb) is added to the protected 17-keto steroid (IIa or IIb) the .alpha.,.beta.-unsaturated .alpha.-chloroaldehyde (IV) is produced in about 90% yield. This is all the more surprising and unexpected because Ficini uses a six member cyclic ketone (cyclohexanone) where less enolization is expected than with the five member cyclic ketones of the protected 17-keto steroids (IIa or IIb).
German Offen. No. 2,521,231 discloses a process of reacting a 17-keto steroid with a lithiated cis-2-alkoxy-1-alkoxyethylene to form a 17.beta.-hydroxy-20,21-dialkoxy-20-unsaturated steroid which is subsequently converted to a 21-alkoxy-.DELTA..sup.16 -20 -keto steroid.
K. S. Y. Lau et al., J. Org. Chem. 43, 1595 (1978), describe the reaction of cis and trans 2-bromo-1-ethoxyethylene with butyl lithium and the subsequent reaction of the lithiated vinyl ether with a ketone to give an .alpha.,.beta.-unsaturated aldehyde. When the cis 2-bromo-1-ethoxyethylene was reacted with butyl lithium, the lithium exchanged with the bromine forming 2-lithio-1-ethoxyethylene. When Lau et al. reacted trans 2-bromo-1-ethoxyethylene with butyl lithium, the lithium exchanged with a proton and formed 2-lithio-2-bromo-1-ethoxyethylene. When Lau et al. reacted this halogenated vinyl ether with cyclopentanone, they obtained the .alpha.-halogenated .alpha.,.beta.-unsaturated aldehyde in 30% yield. In the present invention when cis 2-chloro-1-ethoxyethylene is reacted with butyl lithium the lithium exchanges not with the halogen but with a proton forming 2-lithio-2-chloro-1-ethoxyethylene which when reacted with a 17-keto steroid produces an .alpha.-halogenated .alpha.,.beta.-unsaturated aldehyde. While Lau's process using the cis brominated vinyl ether will not produce any .alpha.-halogenated .alpha.,.beta. -unsaturated aldehyde, the process of the present invention using the corresponding cis chlorinated vinyl ether produces the .alpha.-chlorinated .alpha.,.beta.-unsaturated aldehyde in about 50% yield. While Lau's process using the trans isomer produced the .alpha.-halogenated .alpha.,.beta.-unsaturated aldehyde in only 30% yield, the process of the present invention using trans 2-chloro-1-ethoxyethylene surprisingly and unexpectedly produces the halogenated .alpha.,.beta.-unsaturated aldehyde (IV) in 91.2% yield (Example 1).